Recombination of DNA molecules is a fundamental biological process that influences genetic diversity within a species, repair of DNA damage and gene expression during development, eg. the "uncovering" of recessive oncogenes in certain inherited forms of human cancer. Although considerable progress has been made toward elucidating the mechanism of extrachromosomal recombination events in cultured mammalian cells, less is known about events that occur in the chromosome. A mechanistic understanding of chromosomal recombination is intrinsically important and impacts directly on strategies used for the genetic manipulation of the mammalian genome via homologous recombination (gene targeting). To gain additional insight into homologous chromosomal recombination we will: 1) Determine what step in chromosomal recombination is inhibited by large insertions of heterologous DNA; 2) Apply a direct genetic test to detect and allow study of the repair of heteroduplex DNA intermediates during spontaneous and double-strand break induced intermediates during spontaneous and double-strand break induced intrachromosomal recombination 3) Test the repair, via intrachromosomal and interchromosomal recombination, of double-stranded breaks in DNA produced in vivo; and 4) Develop a system to study spontaneous and carcinogen-induced intragenic recombination between homologous chromosomes.